Imaging bone (flare) responses in APC @ProfPadhani Consultant - - PowerPoint PPT Presentation

Imaging bone (flare) responses in APC

@ProfPadhani

Consultant Clinical Radiologist, Mount Vernon Cancer Centre, London Professor of Cancer Imaging, Institute of Cancer Research, London Co-Chair, International PI-RADS Committee Member St.Gallen APCCC, ASCO APC Imaging Subcommittee

#ICIS2019, Verona, It

APCCC 2019

Active disclosures

Research Support/Agreement Siemens Healthineers Employee None Consultant None Major Stockholder None Speakers Bureau Siemens Healthineers, Janssen, Sanofi, Astellas, Mint Medical Honoraria Siemens Healthineers, Janssen Scientific Advisory Board Siemens Healthineers

Presentation may include discussions of the off-label use of drugs, equipment and software. I am active on twitter @ProfPadhani

BS/CT scans lead to poor confidence for knowing the ‘true’ clinical states & assessing therapy benefits for bone disease in APC with precision

• ncology

implications

• Limited conventional imaging tools

– Unable to accurately predict metastatic disease presence and extent – Unable to identify who is not benefiting early after starting treatment – Limited ability to depict heterogeneity of biologic behavior of bone disease in advancing disease

• Consequences for precision oncology

– Late detection & volume underestimation of metastatic disease (inaccurate tumor volume estimates l inaccurate risk allocations); misdirects therapy approaches – Fail to rapidly detect primary & secondary resistance; impedes patient progress to alternate Rx; increases costs – Heterogeneity of response is increasingly important for predicting patient outcomes

53 YO, mCRPC ; rising PSA (41 to 52ng/ml) on Enzalutamide; new lesions - unconfirmed

Images courtesy Courtesy Nina Tunariu & Johann de Bono: ICR, London

New lesions ‘unconfirmed’ On 1st follow- up study

Unconfirmed new bone scan lesions

• ≈ 20-25% of patients with enzalutamide/abiraterone (PREVAIL/AFFIRM/AA-302)
• New bone scan lesions on the first follow-up scan may represent

1. True progression 2. Tumor ‘momentum’ – temporary worsening disease before delayed ADT response 3. Early favorable osteoblastic reaction (bone scan flare or pseudo-progression)

• PCWG 2+2 Rule: new focal bone scan lesions that develop in the flare period (8-

12 weeks) should be confirmed with the documentation of additional new lesions on the next follow-up scan (in the absence of other signs of progression)

Scintigraphic/healing flare ≈ 15-30% within 3 months when there is clinical benefit

Images courtesy Courtesy Nina Tunariu & Johann de Bono: ICR, London

December 2011 February 2012 November 2012 ….. Rx Enzalutamide continued →

Imaging bone flare reactions in APC

• Development of new focal bone lesion(s) on the 1st follow-up bone scan

(unconfirmed) in the absence of clinical progression, often represents a favorable response to treatment (pseudoprogression)

Morris MJ, et al. Radiographic progression-free survival as a response biomarker in metastatic castration-resistant prostate cancer: COU-AA-302 results. J Clin

• Oncol. 2015;33(12):1356-63

Rathkopf DE, et al. Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial. JAMA Oncol. 2018; 4(5):694-701. Armstrong AJ, et al. The Clinical Impact of New Unconfirmed Bone Scan Lesions in Men with Metastatic 2 Castration-Resistant Prostate Cancer Treated with

• Enzalutamide. JAMA Oncol 2019 [in-press]

?

Survival of patients with early bone scan progression (by 2+2 criteria) who failed to document progression versus those with documented progression on subsequent bone scan

Morris MJ, et al. Radiographic progression-free survival as a response biomarker in metastatic castration-resistant prostate cancer: COU-AA-302 results. J Clin Oncol. 2015;33(12):1356-63

Radiographic progression with abiraterone Rx is associated with poorer survival (COU-AA-302 study) ≥2+2 ≥2+1 or ≥2+0

Unconfirmed new bone scan lesions

Unconfirmed BS lesions on enzalutamide for mCRPC without prior docetaxel (PREVAIL) or after docetaxel (AFFIRM)

No prior docetaxel Prior docetaxel

Armstrong AJ, et al. The Clinical Impact of New Unconfirmed Bone Scan Lesions in Men with Metastatic 2 Castration-Resistant Prostate Cancer Treated with Enzalutamide. JAMA Oncol 2019 [in-press]; ASCO 2019 JCO 37(7_suppl):183-183

New bone scan lesions in chemotherapy-naive men may reflect early treatment response to enzalutamide (avoid premature discontinuation) New BS lesions in post-docetaxel men may reflect true bone scan progression (need direct functional imaging of bone metastasis activity)

Strategies to

• ver-come

limitations of BS imaging flare

BS – 2+2 rule (PCWG) – protocol directed Clinical (including PSA/morphological soft tissue assessments CT scans) Functional imaging

Heterogeneity between clinical and radiographic tumor response – how common?

mHSPC

• Symptoms & PSA are usually

sufficient monitoring tools4

• PSA-discordant progression

(clinical & imaging progression in the absence of a PSA rise) in 30- 45% on ADT/Docetaxel (tumor volume dependent)6

mCRPC

• Symptoms & PSA are commonly

used1, but are increasingly considered inadequate4,5

• PSA-discordant progression 21-30%

can develop radiographic progression without clinical/PSA progression to abiraterone and enzalutamide2,3

1RADAR II guidelines – Crawford ED, Urology 2017; 104:150-159; 2Morris MJ, J Clin Oncol. 2015; 20;33:1356-63; 3Bryce AH,

et al. Prostate Cancer Prostatic Dis 2017 [epub]; 4Gillessen S, et al. Euro Urol. 2018; 73(2):178-211; 4Fitzpatrick JM, et al. Eur J Cancer 2014; 50:1617-27; 4Scher HI, et al. J Clin Oncol. 2016; 34:1-38; 4EAU 2017 Guidelines; 5Padhani AR, et al. Eur Urol 2017; 71:81-92; 6Bryce A, ASCO 2018: abstr 5046

Imaging flare responses in APC (in the absence of clinical evidence of progression)

Modality Mech Therapy Key APC references

Bone scan (BS) Osteoblastic reaction ADT/Abiraterone/ Enzalutamide/ Radium-223 Ryan, CJ, et al. Clin Cancer Res 2011; 17:4854-4861 Keizman D, et al. Prostate Cancer Prostatic Dis. 2017; 20:289-293 Morris MJ, et al. J Clin Oncol. 2015;33(12):1356-63. Rathkopf DE, et al. JAMA Oncol. 2018; 4(5):694-701. Armstrong AJ, et al. JAMA Oncol. 2019 [in-press] NaF PET/CT Osteoblastic reaction ADT/Abiraterone Case reports CT Osteoblastic reaction ADT/Abiraterone

• C. Messiou, et al. Acta Radiol, 2011; 52: 557-561

PSMA PET/CT PSMA upregulation ADT/Abiraterone/ Enzalutamide Aggarwal R, et al. Eur Urol Oncol. 2018; 1:78-82. Zukotynski KA, et al. Clin Nucl Med. 2018 Mar;43(3):213-216. PET/CT – other tracers Non-specificity of tracer Choline

• U. De Giorgi, et al. Oncotarget, 5 (2014), pp. 12448-12458

MRI – morphology Marrow edema Docetaxel/ Radium 223 Personal experience MRI - diffusion

• Not described (yet!)

Week 25 PSA 0.3 Week 37 PSA 0.4 Week 49 PSA 1.5

Retroperitoneal nodes improved. WB-MRI = 1 new bone metastasis BS = no lesions Retroperitoneal nodes

• progressing. New lymphoedema.

WB-MRI = 7 bone lesions BS = 7 lesions (1 on posterior projection)

• mCRPC. Rx Enzalutamide. 2° resistance

Retroperitoneal nodes worse. WB-MRI = 5 bone lesions BS = 2 lesions (outside flare period; needs confirmation)

Date of Oligo-progression Poly-metastatic progression confirmed using PCWG Recorded date of progression

WB-DWI BS

The need to wait to confirm poly metastatic BS lesions (PCWG) before declaring progression delays → BS not suitable for precision oncology Screening PSA 45.5

Retroperitoneal nodes on DWI, No bone lesions

• n BS/CT/MRI

27Feb12 23July12

Hamstra DA, et al, J Clin Oncol 2007: 25:4104-4109

Ex1 Ex2

1500 µm2/s 95 cent of Ex1 (1060 µm2/s)

No Rx effect Highly likely response Likely response

Metastatic prostate cancer (x4 docetaxel, goserelin & prednisone)

DWI: cellular viability habitats can be spatially mapped

Syngo.via Frontier MR Total Tumor Load software v1.3; Siemens Healthineers

Syngo.via Frontier MR Total Tumor Load software v1.3; Siemens Healthineers

Alive = 95% Alive = 35%

b900 MIP with superimposed ADC value classes

1500 µm2/s 1060 µm2/s

Ex1 Ex2

1500 µm2/s 95 cent of Ex1 (1060 µm2/s)

No Rx effect Highly likely response Likely response

mHSPC (x4 docetaxel, ADT & prednisone)

Viability habitats: mapped & quantified (ADC distribution/spatial heterogeneity)

Syngo.via Frontier MR Total Tumor Load software v1.3; Siemens Healthineers

R%=95% R%=35%

b900 MIP with superimposed ADC value classes

1500 µm2/s 1060 µm2/s

Ex1 Ex2

1500 µm2/s 95 cent of Ex1 (1060 µm2/s)

No Rx effect Highly likely response Likely response

Metastatic prostate cancer (x4 docetaxel, ADT & prednisone)

Viability habitats: mapped & quantified (ADC distribution/spatial heterogeneity)

Perez-Lopez R, et al. Multiparametric MRI of Prostate Cancer Bone Disease: Correlation With Bone Biopsy Histological and Molecular Features. Invest Radiol 2018 Feb;53(2):96-102

Cellular infiltrate

• Lower ADC
• High DWI signal
• Lower rF%

ADC nSI rF%

• Somatic mutations in DNA repair pathways

in mCRPC ≈20-25%

• Rx options include PARP inhibitors,

platinum chemotherapy, immunotherapy

• cfDNA for sequencing & Rx selection,

therapy monitoring, resistance mechanism

• Imaging: localisation of biopsy site before

& at therapy resistance, monitoring Rx response

BRCA2 mutation BRCA2 reversed

27Feb12 PSA 93.8 15Jan13 PSA 25.5 16Aug13 PSA 87.0 03Jun13 PSA 40.1 23July12 PSA 9.9 12Nov12 PSA 6.9

Baseline x4 Docetaxel x 10 Docetaxel Monitor x3 Carbazitaxel x6 Carbazitaxel

03Jan14 PSA 25.5

Abiraterone RT

b900 SI

Syngo.via Frontier MR Total Tumor Load software v1.3; Siemens Healthineers; WIP

ADC classes 95% 24% 76% 58% 82% 28.6% 65%

ADC classes Alive Dying Dead

Radium-223: Disease response and fracture assessment by whole body diffusion-weighted MRI in mCRPC Parker CC, et al. JCO 36, no. 15_suppl (May 20, 2018) 5024-5024. Marked heterogeneity between lesions and patients at both Ra-223 doses

NextGen Imaging promotes Precision Oncology Trials

Test in prostate cancer Therapy implications MSI, Mismatch repair (MMR) gene mutation Immunotherapy (FDA approved)

DNA Repair Status. ‘BRACAness’ assays for BRCA1/2/ATM, PALB2 - mutations/loss or HR signatures useful for platinum or PARPi Loss of AR (AR-v7, mutations) Lack of response to AR directed therapy cfDNA/ctDNA Prognostic value PTEN loss AKT inhibitor responses with AR inhibitors CDK12 loss Cell cycle checkpoint inhibitors Loss of TP52/RB1 Short duration of response to AR directed therapies; possible response to platinum CTC heterogeneity Response to docetaxel vs AR directed therapies Neuroendocrine tumor Platinum chemotherapy PSMA expression PSMA directed therapies

TP2 TP3 TP7 TP6 TP5 TP4 TP8 TP9 TPx TPx TPx TPx

Rx1 Rx2 Rx3 Rx4 Measures of tumor activity Treatment response assessments in the era of precision oncology: Right treatment, for the right patient, at the right time, for the right duration

Next generation diagnostics (imaging, genomics, blood, serum, tissue samples)

Imaging (volume, distribution, viability, response, receptors, metabolism) CTCs/cfDNA/ctDNA/ guided biopsy Immunohistochemistry (IHC) & FISH Tumor markers Biochemistry Combination BMs

Prognostic or predictive genomic tests poised for clinical decision making in APC

@MarkRubin GU-ASCO2019

Which NextGen Imaging method & when?

Localized prostate cancer (low/intermediate/high risk) Hormone sensitive prostate cancer (HSPC) – normal testosterone Castration resistant prostate cancer (CRPC) – low testosterone

BCR De novo M1 M+/++ M0 CRPC M+ CRPC M++CRPC M0

Suspected cancer

1st line Rx High-risk locally advanced M0/M1

APC grouping

Low-risk

@ProfPadhani

Intermediate risk subgroups/ high risk localised

(mp)MRI for detection, staging & local restaging PET/CT for oligometastases detection and restaging for Rx decisions WB-MRI/DWI for poly-metastatic disease staging & treatment monitoring

Take home points: Time to move on to NextGen Imaging Don’t rely on CT/BS for (bone) metastatic assessments

Next generation imaging PET-CT (various tracers) & whole-body MRI/DWI can detect bone metastases with high sensitivity; early detection of metastases & therapy resistance can have positive precision oncology therapy implications NextGen imaging can positively assess therapy response and early failure, unlike bone scans which only identify late tumor progression. Accurate therapy assessments & heterogeneity can promote the development and clinical use of targeted therapies NextGen imaging directed therapy survival benefits in APC has not been evaluated, but methods are ready for clinical trials incorporation*

*Padhani AR, et al. METastasis Reporting And Data System for Prostate cancer (MET-RADS-P): Practical guidelines for acquisition, interpretation, and reporting of Whole-body MRI based evaluations of multiorgan involvement in advanced prostate cancer. Eur Urol. 2017 Jan;71(1):81-92. *Fendler WP, et al. (68)Ga-PSMA PET/CT: Joint EANM and SNMMI procedure guideline for prostate cancer imaging: version 1.0. Eur J Nucl Med Mol Imaging. 2017 Jun;44(6):1014-1024.